Targeted photoacoustic imaging of VEGF receptors in angiogenic vasculature

描述(申请人提供)：我们建议开发一种针对血管内皮生长因子(VEGFR)受体的光声成像造影剂，以便通过VEGFR介导的内吞作用在肿瘤内皮细胞中积聚和保留。VEGFR从肿瘤发展的早期起就在血管生成的肿瘤血管中过度表达，因此VEGFR成像可以用于早期诊断以及图像引导的抗血管生成治疗的优化和管理。为了加强光到声信号的转换，提高光声成像检测体内VEGFR异常水平的灵敏度，我们将近红外荧光染料吲哚青绿复合到树枝状大分子支架上，然后将衍生的树枝状大分子偶联到血管内皮生长因子上。我们将在已建立的肿瘤血管重塑模型中测试该示踪剂对VEGFR的光声成像，以响应抗血管生成治疗。在这个项目中，我们结合了三个团队的专业知识和成果，他们是开发血管新生血管中VEGFR成像的靶向示踪剂的专家，肿瘤病变的光声成像的创新成像硬件和软件，以及用于成像的ICG的新型衍生品。这项研究将提供一流的靶向PAI示踪剂，并建立肿瘤血管中血管内皮生长因子受体的靶向光声成像的可行性。如果成功，可能会为深度小于2-3厘米的癌症病变提供一种安全且成本效益高的核成像替代方案。在第二阶段，我们将建立这种示踪剂的可行性，用于相对较深的肿瘤病变的早期诊断，区分良恶性病变，并进行该示踪剂的后期临床前开发。 公共卫生相关性：血管内皮生长因子受体(VEGFR)从肿瘤发展的早期就在血管生成的肿瘤血管中过度表达，因此VEGFR成像可以用于早期诊断和图像引导的抗血管生成治疗的优化。我们建议开发一种针对这些受体的光声成像造影剂，这样它就可以通过特异性受体介导的内吞作用在肿瘤内皮细胞中积累和保留。为了增强光到声信号的转换，提高检测的灵敏度，我们将近红外荧光染料吲哚青绿复合到树枝状大分子支架上，然后将衍生的树枝状大分子与靶向蛋白-血管内皮生长因子进行定点偶联。我们将在已建立的肿瘤血管重塑模型中测试该示踪剂对VEGFR的光声成像，以响应抗血管生成治疗。因此，这项研究将为VEGFR的光声成像提供一流的靶向示踪剂，并可能成为检测深度小于2-3厘米的癌症病变的安全、经济有效的核成像替代方案。

DESCRIPTION (provided by applicant): We propose to develop a contrast agent for photoacoustic imaging targeted to the receptors of vascular endothelial growth factor (VEGFR), so it can be accumulated and retained in tumor endothelial cells by VEGFR-mediated endocytosis. VEGFR are over expressed in angiogenic tumor vasculature from the very early stages of tumor development and therefore VEGFR imaging can be used for early diagnosis as well as for image-guided optimization and management of anti-angiogenic therapy. In order to enhance conversion of light into acoustic signal and increase the sensitivity of detection of abnormal levels of VEGFR in vivo by photoacoustic imaging, we will multiplex near-infrared fluorescent dye indocyanine green on a dendrimer scaffold, and then conjugate the derivatized dendrimer to VEGF. We will test this tracer for photoacoustic imaging of VEGFR in the established model of tumor vascular remodeling in response to anti-angiogenic therapy. For this project we combine the expertise and achievements of three groups, the experts in developing of targeted tracers for imaging of VEGFR in angiogenic vasculature, innovative imaging hardware and software for photoacoustic imaging of tumor lesions, and novel derivatives of ICG for imaging. This study will provide the first-in-class targeted PAI tracer and establish the feasibility of targeted photoacoustic imaging of VEGF receptors in tumor vasculature. If successful, might provide a safe and cost-effective alternative to nuclear imaging for cancerous lesions located at the depths less than 2-3 cm. In Phase II we will establish feasibility of this tracer for early diagnostic of relatively deep tumor lesions, discrimination of malignant and benign lesions, and perform late pre-clinical development of the tracer. PUBLIC HEALTH RELEVANCE: Receptors of vascular endothelial growth factor (VEGFR) are over expressed in angiogenic tumor vasculature from the very early stages of tumor development, therefore VEGFR imaging can be used for early diagnosis and image-guided optimization of anti-angiogenic therapy. We propose to develop a contrast agent for photoacoustic imaging that will be targeted to these receptors, so it can be accumulated and retained in tumor endothelial cells by specific receptor-mediated endocytosis. In order to enhance conversion of light into acoustic signal and increase the sensitivity of detection, we will multiplex a near-infrared fluorescent dye indocyanine green on a dendrimer scaffold, and then site-specifically conjugate the derivatized dendrimer to targeting protein, VEGF. We will test this tracer for photoacoustic imaging of VEGFR in the established model of tumor vascular remodeling in response to anti-angiogenic therapy. Thus study will provide the first-in-class targeted tracer for photoacoustic imaging of VEGFR, and might enable a safe, cost-effective alternative to nuclear imaging for detection of cancerous lesions located at the depths less than 2-3 cm.